Chemically, ziprasidone is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one having the structural Formula I. It is indicated for the treatment of schizophrenia. Ziprasidone is commercially available in the form of its hydrochloride salt.

U.S. Pat. No. 4,831,031 discloses a process for the preparation of ziprasidone hydrochloride, which involves refluxing N-(1,2-benzisothiazol-3-yl)piperazine with 5-(2-chloroethyl)-6-chloro-oxindole in methyl isobutyl ketone in the presence of sodium iodide and sodium carbonate for about 40 hours followed by column chromatographic purification of the product to get ziprasidone base which is dissolved in methylene chloride and treated with ethereal hydrogen chloride to get ziprasidone hydrochloride salt. The salt is washed with acetone and the product is dried.
U.S. Pat. No. 5,312,925 discloses a process for the preparation of ziprasidone hydrochloride, which involves heating to reflux a mixture of 5-(2-chloroethyl)-6-chloro-oxindole and 1-(1,2-benzisothiazol-3-yl)piperazine in aqueous sodium carbonate for 14 hours, followed by cooling to 20° C. and filtration. The wet product is re-slurried in isopropyl alcohol and filtered, washed with fresh isopropyl alcohol followed by drying under vacuum to get ziprasidone base. The base is then treated with aqueous hydrochloric acid in the presence of water at a temperature of about 60-65° C. for 3 to 24 hours, followed by filtration, washing with water and drying under vacuum to get ziprasidone hydrochloride.
U.S. Pat. Nos. 5,206,366 and 5,338,846 disclose a process for the preparation of ziprasidone base, which involves heating to reflux a mixture of 5-(2-chloroethyl)-6-chloro-oxindole and 1-(1,2-benzisothiazol-3-yl)piperazine in aqueous sodium carbonate for 13 hours followed by cooling to 25° C. and filtration. The product is re-slurried in isopropyl alcohol twice and then filtered and dried under vacuum. The dried product is recrystallized from tetrahydrofuran to get ziprasidone base having a purity of 99.7% measured by HPLC.
U.S. Pat. No. 6,150,366 discloses a process for the preparation of ziprasidone hydrochloride from double recrystallized ziprasidone base having a purity of about 99.7% by HPLC. The process involves refluxing a slurry of ziprasidone base in tetrahydrofuran and water to get a clear solution followed by addition of aqueous hydrochloric acid solution at 60-62° C. in two lots, cooling the mixture to 13° C. to complete crystallization of ziprasidone hydrochloride. The product is filtered and washed with fresh cold tetrahydrofuran.
The prior art approach for the preparation of ziprasidone or a pharmaceutically acceptable salt thereof is not suitable from a commercial point of view because the product is not obtained in high purity and is not color stable, thus making the approach commercially difficult to implement. The purity hereto refers to the compound purity.
To achieve a high efficiency of reaction for industrial scale synthesis of ziprasidone hydrochloride, it is necessary to minimize the formation of the impurities.
The present inventors have found that these problems associated with prior art could be attributed to non-effective removal of trapped hydrogen chloride from the reaction product. The entrapped hydrogen chloride leads to degradation of ziprasidone hydrochloride and leads to the formation of the impurities, which both darken the color and increase the impurity content. These impurities have been identified in the product as isopropylene ziprasidone and mesityl oxide impurities.
Thus, the present invention provides a process which does not result in impure ziprasidone or a pharmaceutically acceptable salt thereof; rather pure ziprasidone having impurity less than 0.1% is obtained. The ziprasidone hydrochloride when made by the process of the present invention is color stable and easy to handle thus making the process amenable for commercial scale use.